Purpose: Developmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 310 of which were sequenced as proband-parent trios. Methods: Exomes were generated for 365 individuals (127 affected) and genomes were generated for 612 individuals (244 affected). Results: Diagnostic variants were found in 102 individuals (27%), with variants of uncertain significance in an additional 44 (11.8%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the diagnostic rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have reclassified 15 variants, with 10.8% of families who initially received a VUS, and 4.7% of families who received no variant, subsequently given a diagnosis. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP. Conclusion: Our results strongly support the value of genome sequencing as a first-choice diagnostic tool and means to continually advance clinical and research progress related to developmental disabilities, especially when coupled to rapid and free data sharing.